Cefdinir is a third generation cephalosporin antibiotic for oral administration and has a broader antibacterial spectrum over the general gram positive and gram negative bacteria, especially against Streptococci, than other antibiotics for oral administration.
In view of the vital antibiotic activities of cefdinir of the formula (I), various methods of preparation were reported. Cefdinir is for the first time claimed in U.S. Pat. No. 4,559,334 and the nature of the product that is disclosed in this patent is described as crystalline like amorphous in subsequent US patent (U.S. Pat. No. 4,935,507). This patent also discloses a process for the preparation of cefdinir as depicted in the Scheme I.

In the disclosed process, 7-amino-3-vinyl-3-cephem-4-carboxylic acid ester where R represents a conventional carboxy protecting group, is acylated with the reactive ester of haloacylacetic acid, which was converted to its oxime, followed by cyclization with thiourea and deprotection of the ester group to afford cefdinir. The product obtained by the process described in examples 14 and 16 is approximately 80–85% pure. The cyclization step suffers from poor yield and affords brownish color of the thiazole derivative, which subsequently affords cefdinir, but quality and yield were inferior. Further, owing to the fact that the expensive 7-amino-3-vinyl-3-cephem-4-carboxylic acid is carried through four steps, cost of producing cefdinir is high.
U.S. Pat. No. 4,935,507 claims the novel crystalline form of the cefdinir syn-isomer and a process for preparing the same. The X-ray crystallography data given in this patent is given in the following table:
2 θ ° ValuesRelative Intensity14.77617.85621.510022.07023.43824.48028.040The crystalline form (Crystal A) of U.S. Pat. No. 4,935,507 is prepared from the syn-isomer prepared according to the procedures described in Examples 14 and 16 of U.S. Pat. No. 4,559,334.
In our U.S. Pat. No. 6,388,070, we disclosed a process for preparing a compound of formula (VIII), wherein, R1 represents H, trityl, etc., R2 represents H, phenyl, etc., R3 represents CH3, CH═CH2, etc., R4 is H or a salt or a carboxylic protecting group; R5 is H or trimethylsilyl; comprising acylating the compound of formula (VI) with compound of formula (VII) in the presence of an organic solvent, organic base and a silylating agent at a temperature in the range of −10° C. to +30° C. The reaction is shown in scheme II below:

U.S. Pat. No. 6,093,814 discloses a process for the preparation of cefdinir and its intermediate as represented in Scheme III:

In this process p-methoxybenzyl 7-amino-3-vinyl-3-cephem-4-carboxylate is condensed with 2-mercaptobenzothiazolyl (Z)-(2-amino-4-thiazolyl)-2-(trityloxyimino)acetate in N,N-dimethyl acetamide, and the product obtained was treated with p-toluenesulfonic acid in the presence of a mixture of diethyl ether and methanol to get crystalline 7-[(2-amino-4-thiazolyl)-2-(Z)-(trityloxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylic acid.pTSA.2DMAc solvate. This process utilizes highly volatile, low-boiling and therefore industrially-not-preferred solvent, diethyl ether, for crystallizing out the above solvate. In addition, the quantity of the low-boiling solvent used is also very high ranging from 60–100 volumes, thereby adding hazard to the operations. Added to this is the fact that the recovery of these solvents from their mixture is not straight-forward.
U.S. Pat. No. 6,350,869 discloses the purification of impure cefdinir through the preparation of N,N-dicyclohexylamine salt of 7-[2-amino-4-thiazolyl-2-(z)-hydroxyimino acetamido]-3-vinyl-3-cephem-4-carboxylic acid and subsequent hydrolysis to get pure cefdinir. This process requires the preparation of crude cefdinir, conversion to N,N-dicyclohexylamine salt and then hydrolysis of the salt to get pure cefdinir, and therefore the overall yield is not attractive.
U.S. Pat. No. 6,350,869 also emphasizes that cefdinir is unstable in the presence of other amines, with which, it gets heavily degraded. In addition, Yoshihiko Okamoto et al. (J. Pharm. Sci. Vol. 8(9), 976, 1996) report that cefdinir may be unstable under basic environment.
Crystalline cefdinir has limitations in formulation development as it cannot be developed into tablets.
Considering the foregoing limitations, we undertook an investigation in our lab to develop a product which is easy to handle and convenient to develop a dosage which is easily absorbable. We also parallel undertook an investigation to identify a process, which involves (i) less number of steps, (ii) the direct isolation of cefdinir, with out the need to prepare crude cefdinir in an additional step. This would permit commercializing the production of high-pure cefdinir with industrial-friendly solvent, which can further be recovered for recycling.